Methods for treating alzheimer's disease   

Abstract: Provided herein arc PAK inhibitors. Also provided herein are compositions and methods for treating an individual suffering from Alzheimer's disease.

This application claims priority to U.S. Provisional Application No. 61/250,350, entitled, “Methods for Treating Alzheimer\'s Disease,” filed on Oct. 9, 2009, the contents of which are incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Alzheimer\'s disease (AD) is a progressive neurodegenerative disease characterized by progressive loss of cognition, and decreasing ability to control movement or bodily functions.

SUMMARY

Described herein are p21-activated kinase (PAK) inhibitors that halt or delay the progression of some or all symptoms of Alzheimer\'s disease (AD). In certain cases, Alzheimer\'s disease is initially diagnosed upon a finding of early dementia in the clinic. Progressive deterioration leads to moderate dementia and then advanced dementia in late stages of the disease. In some embodiments, the PAK inhibitors described herein halt or delay the progression of early stage Alzheimer\'s disease. In some embodiments, the PAK inhibitor described herein halt or delay the progression of middle stage Alzheimer\'s disease. In some embodiments, the PAK inhibitor described herein halt or delay the further deterioration in late stage Alzheimer\'s disease. In some embodiments, the PAK inhibitors described herein stabilize or alleviate or reverse symptoms of Alzheimer\'s disease. In some embodiments, PAK inhibitors described herein provide therapeutic benefit to an individual suffering from Alzheimer\'s disease that is non-responsive to conventional therapy (e.g., treatment with anticholinergics, antipsychotics or the like).

In some instances, PAK inhibition modulates spine morphogenesis. In some instances, PAK inhibitors modulate spine morphogenesis thereby modulating loss of synapses associated with Alzheimer\'s disease. In some instances, aberrant spine morphogenesis (e.g., abnormal spine density, length, thickness, shape or the like) is associated with pathogenesis of Alzheimer\'s disease. In some instances, administration of a PAK inhibitor to individuals diagnosed with or suspected of having Alzheimer\'s disease reduces, stabilizes or reverses abnormalities in dendritic spine morphology, density, and/or synaptic function, including but not limited to abnormal spine density, spine size, spine shape, spine plasticity, spine motility or the like. In some instances, administration of a PAK inhibitor to individuals diagnosed with or suspected of having Alzheimer\'s disease reduces, stabilizes or reverses depression of synaptic function caused by beta-amyloid protein.

Provided herein are methods for delaying or halting progression of Alzheimer\'s disease comprising administering to an individual in need thereof a therapeutically effective amount of a p21-activated kinase (PAK) inhibitor.

In some embodiments of the methods described herein, the Alzheimer\'s disease is early stage, middle stage or late stage Alzheimer\'s disease. In some embodiments, the Alzheimer\'s disease is associated with early dementia, moderate dementia or advanced dementia.

In some embodiments of the methods described herein, the p21-activated kinase (PAK) inhibitor modulates dendritic spine morphology or synaptic function.

In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine density. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine length. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine neck diameter. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine shape. In some embodiments, the p21-activated kinase (PAK) inhibitor increases the number of mushroom-shaped dendritic spines. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine head volume. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates dendritic spine head diameter. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates the ratio of the number of mature spines to the number of immature spines. In some embodiments, the p21-activated kinase (PAK) inhibitor modulates the ratio of the spine head volume to spine length.

In some embodiments, the p21-activated kinase (PAK) inhibitor modulates synaptic function. In some embodiments, the p21-activated kinase (PAK) inhibitor normalizes or partially normalizes aberrant baseline synaptic transmission associated with Alzheimer\'s disease. In some embodiments, the p21-activated kinase (PAK) inhibitor normalizes or partially normalizes aberrant synaptic plasticity. In some embodiments, the p21-activated kinase (PAK) inhibitor normalizes or partially normalizes aberrant long term depression (LTD) associated with Alzheimer\'s disease. In some embodiments, the p21-activated kinase (PAK) inhibitor normalizes or partially normalizes aberrant long term potentiation (LTP) associated with Alzheimer\'s disease. In some embodiments, the p21-activated kinase (PAK) inhibitor normalizes or partially normalizes deficits in memory, executive function, or language. In some embodiments, the p21-activated kinase (PAK) inhibitor reverses or partially reverses dementia or paraphasia.

In some embodiments of the methods described above, a therapeutically effective amount of a p21-activated kinase (PAK) inhibitor causes substantially complete inhibition of one or more p21-activated kinases. In some embodiments of the methods described above, a therapeutically effective amount of a p21-activated kinase (PAK) inhibitor causes partial inhibition of one or more p21-activated kinases.

In some embodiments, the p21-activated kinase (PAK) inhibitor is a Group I PAK inhibitor. In some embodiments, the p21-activated kinase (PAK) inhibitor is a PAK1 inhibitor. In some embodiments, the p21-activated kinase (PAK) inhibitor is a PAK2 inhibitor. In some embodiments, the p21-activated kinase (PAK) inhibitor is a PAK3 inhibitor.

In some embodiments, the methods described above further comprise administration of a second therapeutic agent. In some embodiments, wherein the second therapeutic agent is an acetylcholinestrase inhibitor, memantine or minocycline. In some embodiments, the second therapeutic agent is an alpha7 nicotinic receptor agonist. In some embodiments, the second therapeutic agent is a gamma secretase inhibitor. In some embodiments, the second therapeutic agent is a beta secretase inhibitor.

In some embodiments of the methods described above, administration of a p21-activated kinase (PAK) inhibitor to an individual in need thereof improves, stabilizes, or lessens the deterioration of scores on the Mini-Mental State Exam (MMSE) or Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) scale for the individual.

Provided herein are methods of reducing, stabilizing, or reversing neuronal withering and/or loss of synaptic function associated with Alzheimer\'s disease comprising administering to an individual in need thereof a therapeutically effective amount of an agent that modulates dendritic spine morphology or synaptic function.

In some embodiments, the neuronal withering and/or loss of synaptic function is induced by beta-amyloid protein, or proteolytic or hydrolysis products thereof, neurofibrillary tangles, amyloid tangles or hyperphosphorylated tau protein. In some embodiments, the neuronal withering or loss of synaptic function is associated with dimers or oligomers of beta-amyloid protein. In some embodiments, the dimers or oligomers of beta-amyloid protein are soluble in physiological fluids (e.g., cerebrospinal fluid, plasma, or the like). In some embodiments, the dimers or oligomers of beta-amyloid protein are insoluble in physiological fluids.

Also provided herein are methods of reducing, stabilizing or reversing atrophy or degeneration of nervous tissue in the brain associated with Alzheimer\'s disease comprising administering to an individual in need thereof a therapeutically effective amount of an agent that modulates dendritic spine morphology or synaptic function. In some embodiments, the atrophy or degeneration of nervous tissue is in the temporal lobe, the parietal lobe, the frontal cortex or the cingulate gyrus.

In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine density. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine length. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine neck diameter. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine shape. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function increases the number of mushroom-shaped dendritic spines. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine head volume. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates dendritic spine head diameter. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates the ratio of the number of mature spines to the number of immature spines. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function modulates the ratio of the spine head volume to spine length.

In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function normalizes or partially normalizes aberrant baseline synaptic transmission associated with Alzheimer\'s disease. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function normalizes or partially normalizes aberrant synaptic plasticity. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function normalizes or partially normalizes aberrant long term depression (LTD) associated with Alzheimer\'s disease. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function normalizes or partially normalizes aberrant long term potentiation (LTP) associated with Alzheimer\'s disease. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function normalizes or partially normalizes deficits in memory, executive function, or language. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function reverses or partially reverses dementia or paraphasia. In some embodiments of the above methods, the agent that modulates dendritic spine morphology or synaptic function is a p21-activated kinase (PAK) inhibitor.

In some embodiments of any of the above methods, administration of a p21-activated kinase (PAK) inhibitor to an individual in need thereof improves, stabilizes, or lessens the deterioration of scores on the Mini-Mental State Exam (MMSE) or Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) scale for the individual.

Provided herein are methods for determination of an effective dose of a p21-activated kinase (PAK) inhibitor for treatment of Alzheimer\'s disease comprising: i) using an analytical instrument to detect and measure the amount of soluble beta-amyloid protein, or hydrolysis products thereof, in a sample of cerebrospinal fluid (CSF); and ii) increasing or decreasing or maintaining the dose of the p21-activated kinase (PAK) inhibitor based on the measurement of the amount of soluble beta-amyloid protein, or hydrolysis products thereof, in the sample of cerebrospinal fluid (CSF).

Provided herein are methods for delaying or preventing the onset of Alzheimer\'s disease comprising administration of a p21-activated kinase (PAK) inhibitor to an individual in need thereof. In some embodiments, the individual has or is suspected of having risk genes pre-disposing the individual to the development of Alzheimer\'s disease.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 describes illustrative LTP recorded in C57/black 6 mice temporal cortex slices in the presence of 1 μM Compound G.

FIG. 2 describes illustrative LTP recorded in C57/black 6 mice temporal cortex slices in the presence of 1 μM Compound A.

FIG. 3 describes illustrative shapes of dendritic spines.

FIG. 4 illustrates a neuropsychological screening test used in diagnosis of Alzheimer\'s disease.

DETAILED DESCRIPTION

Provided herein are methods for treatment of Alzheimer\'s disease comprising administration of PAK inhibitors described herein Alzheimer\'s disease is a progressive terminal neurodegenerative disease. Current treatment modalities for Alzheimer\'s disease reduce the severity of disease symptoms but do not halt or delay progression of the disease. Current disease-modifying approaches for the treatment of Alzheimer\'s disease include decreasing beta-amyloid protein load (e.g., by reducing beta-amyloid protein production via inhibition of secretases), increasing clearance of beta-amyloid plaques, or reducing beta-amyloid protein aggregation. In some instances, amyloid-related mechanisms prune neuronal spines in the brain and contribute to neuronal withering associated with Alzheimer\'s disease. PAK inhibitors described herein modulate dendritic spine morphology, dendritic spine density and/or synaptic function thereby delaying or halting progression of Alzheimer\'s disease and provide an advantage over current treatment protocols for Alzheimer\'s disease. In some instances, PAK inhibitors described herein improve cognition and/or memory deficits associated with Alzheimer\'s disease thereby improving overall quality of life and/or life expectancy of individuals suffering from early, middle or late stage Alzheimer\'s disease.

In some embodiments, PAK inhibitors described herein halt or slow down progressive degeneration of neural tissue. In some embodiments, PAK inhibitors described herein halt or delay progressive atrophy of nervous tissue in the brain. In some instances, PAK inhibitors described herein reduce or halt neuronal withering caused by beta amyloid protein-related mechanisms. In some embodiments, PAK inhibitors reverse defects in synaptic function and plasticity in a patient diagnosed with Alzheimer\'s disease. In some embodiments, PAK inhibitors reverse defects in synaptic function and plasticity in a patient diagnosed with Alzheimer\'s disease before Abeta plaques are detected. In some embodiments, PAK inhibitors reverse defects in synaptic morphology, synaptic transmission and/or synaptic plasticity induced by soluble Abeta dimers and/or oligomers. In some embodiments, PAK inhibitors reverse defects in synaptic morphology, synaptic transmission and/or synaptic plasticity induced by Abeta oligomers and/or Abeta-containing plaques. In some embodiments, PAK inhibitors described herein modulate dendritic spine length. In some embodiments, PAK inhibitors described herein modulate dendritic spine length and/or spine head diameter, thereby reversing or alleviating memory, vocabulary and/or cognitive deficits in individuals suffering from Alzheimer\'s disease.

In some instances, dendritic spine head size influences spine motility and/or stability. In some instances, beta-amyloid protein oligomers induce defects in dendritic spines with subsequent development of Alzheimer\'s pathology. In some instances an increase in dendritic spine head volume and/or spine head surface area and/or spine head diameter increases synaptic function and reduces or reverses loss of synapses caused by Alzheimer\'s pathology. In some instances, a small spine head diameter results in reduced synaptic transmission and/or plasticity. In some embodiments, PAK inhibitors described herein increase dendritic spine head diameter, thereby normalizing or partially normalizing signaling at synapses. In some instances, an increase in the number of mushroom shaped spines enhances synaptic signaling thereby alleviating or reversing the effects of neuronal degeneration and/or withering. In some instances, PAK inhibitors described herein decrease the number of immature long spines and/or reduce the length of dendritic spines. In some instances, a reduction in the number of long spines and/or a reduction in dendritic spine length alleviates, stabilizes or reverses some or all symptoms of Alzheimer\'s disease.

Studies have shown that within plaque dendrites, spine density is lower than the spine density in normal (e.g., non-plaque) dendrites (Knafo, S. et al, Cereb Cortex. 2009; 19(3):586-92). Accordingly, PAK inhibitors described herein alter the ratio of spine formation to elimination, thereby increasing spine density within plaques. Within plaques, studies have shown that there is a decrease in density of small-headed spines (head volume <0.05 μm3) compared to density of small-headed spines in normal dendrites. In some instances, small-headed spines dynamically change to medium-headed (head volume 0.05-0.1 μm3) or large-headed spines (head volume >0.1 μm3). In some instances, medium-headed or large-headed spines are associated with increased synaptic contacts. In some embodiments, PAK inhibitors described herein increase spine head volume and/or diameter within plaques thereby improving synaptic contacts within plaques. Further, studies suggest that within plaques, there is a decrease in the frequency of large spines that are associated with traces of long-term memory. Accordingly, PAK inhibitors described herein increase spine size within plaques, thereby alleviating cognitive deficits associated with Alzheimer\'s disease and/or halting or delaying further progression of Alzheimer\'s disease.

Described herein are PAK inhibitors and compositions thereof that alleviate, stabilize or reverse some or all symptoms of Alzheimer\'s disease. Also described herein are methods of treatment of Alzheimer\'s disease comprising administration of PAK inhibitors and/or compositions thereof to individuals in need thereof, that alleviate, stabilize or reverse some or all neuronal withering and/or loss of synaptic function associated with Alzheimer\'s disease. Described herein is the use of PAK inhibitors (e.g., any PAK inhibitor described herein including compounds of Formula I-XXIII) in the manufacture of a medicament for the treatment of early, middle or late stage Alzheimer\'s disease. Described herein is the use of PAK inhibitors (e.g., any PAK inhibitor described herein including compounds of Formula I-XXIII) in the manufacture of a medicament for modulating (e.g., stabilizing, alleviating or reversing) aberrant spine morphology and/or aberrant synaptic function that is associated with Alzheimer\'s disease. Described herein is the use of PAK inhibitors (e.g., any PAK inhibitor described herein including compounds of Formula I-XXIII) in the manufacture of a medicament for stabilizing, alleviating or reversing neuronal withering and/or atrophy and/or degeneration of nervous tissue that is associated with Alzheimer\'s disease.

In some embodiments, the PAK inhibitors described herein alleviate, stabilize or reverse symptoms of Alzheimer\'s disease in an individual that is non-responsive to conventional therapy (e.g., treatment with anticholinergics, antipsychotics). The current standard of care for treatment of Alzheimer\'s disease includes the use of anticholinergics, antipsychotics and/or NMDA receptor antagonists for management of disease symptoms. In some instances, anticholinergics reduce death of cholinergic neurons. In some instances, NMDA receptor antagonists reduce excitotoxicity (caused, for example, by over stimulation of glutamate receptors) associated with Alzheimer\'s disease in neural tissue. In some instances, antipsychotic agents reduce aggression associated with Alzheimer\'s disease. In some embodiments, PAK inhibitors described herein are administered in combination with a second therapeutic agent (e.g., an anticholinergic agent) and provide an improved therapeutic outcome compared to therapy with the second therapeutic agent alone.

In some instances, Alzheimer\'s disease is associated with abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density and/or abnormal synaptic function. In some instances, PAK kinase activity has been implicated in defective spine morphogenesis, maturation, and maintenance. In some instances, soluble Abeta dimers and/or oligomers increase PAK kinase activity at the synapse. In some instances, Abeta plaques and/or insoluble Abeta aggregates increase PAK kinase activity at the synapse. Described herein are methods for suppressing or reducing PAK activity by administering a PAK inhibitor for rescue of defects in spine morphology, size, plasticity spine motility and/or density associated Alzheimer\'s disease as described herein. Accordingly, in some embodiments, the methods described herein are used to treat an individual suffering from Alzheimer\'s disease wherein the disease is associated with abnormal dendritic spine density, spine size, spine plasticity, spine morphology, spine plasticity, and/or spine motility or a combination thereof.

In some embodiments, a p21-activated kinase inhibitor described herein modulates abnormalities in dendritic spine morphology and/or synaptic function that are associated with Alzheimer\'s disease. In some embodiments, modulation of dendritic spine morphology and/or synaptic function alleviates or reverses memory loss, dementia, deficits in executive function, and/or deficits in language (for example, loss of vocabulary and paraphasias) associated with Alzheimer\'s disease.

Alzheimer\'s disease is characterized by symptoms of memory loss in the early stages of the disease. As the disease advances, symptoms include confusion, long-term memory loss, paraphasia, loss of vocabulary, aggression, irritabilty and mood swings. In more advanced stages of the disease, there is loss of bodily functions. Alzheimer\'s disease is a progressive terminal disease and is often fatal within about seven years of diagnosis.

In some instances, behavioral assessments, cognitive tests and brain scans aid in a definitive diagnosis of early stage Alzheimer\'s disease. For example, PET scans of a person with Alzheimer\'s disease show a loss of function in the temporal lobe. Other diagnostic methods include Single photon emission computed tomography (SPECT) scans and neuropsychological screening tests. FIG. 4 shows an example of a neuropsychological screening test used in diagnoses of Alzheimer\'s disease. Patients are asked to copy drawings such as the drawing in FIG. 4. Progressive deterioration causes moderate dementia. In some instances tasks requiring complex motor sequences become less coordinated and memory deficits are evident during mid and late stages of the disease. In mid-stages of the disease, behavioral changes are prevalent including wandering, sundowning, delusions and aggression. Urinary continence may develop in mid-stages of Alzheimer\'s disease. In some instances, there is a substantial loss of speech in advanced stages of the disease along with loss of muscle mass, mobility and control of bodily functions.

In some instances, development of Alzheimer\'s disease is associated with a genetic component. Certain risk alleles and genes that have been identified for Alzheimer\'s disease include mutations in Amyloid Precursor Protein (APP), mutations in presenilin 1 and 2, the epsilon4 allele, the 91 bp allele in the telomeric region of 12q, Apolipoprotein E-4 (APOE4) gene, SORL1 gene, reelin gene or the like. In some instances, several risk alleles or genes are involved in etiology of the disease. In some instances, Alzheimer\'s disease runs in families and creates a predisposition or vulnerability to the illness. In some instances, a combination of genetic, familial and environmental factors play a role in manifestation of disease symptoms. In some instances, mutations in genes resulting in a predisposition to Alzheimer\'s leads to early-onset of the disease.

In some instances, Alzheimer\'s disease is associated with production and/or aggregation of Abeta peptides. Abeta peptides are generated from APP (Amyloid Precursor Protein) through proteolytic cleavage. APP can be cleaved by enzymes of the secretase family (alpha, beta- and gamma-secretase). In some instances, Abeta peptides induce defects in synaptic morphology and/or function, leading to the development of Alzheimer\'s disease. In some instances, the Abeta species is Abeta42. In some instances, mutations in APP associated with early-onset Alzheimer\'s increase production of Aβ42. In some instances, methods provided herein reduce or delay the production of Abeta42 species. In some instances, methods provided herein modulate the production of Abeta40 species.

In some instances, cellular changes in brain cells contribute to pathogenesis of Alzheimer\'s disease. In some instances, an abnormality in dendritic spine density in the brain contributes to the pathogenesis of Alzheimer\'s disease. In some instances, a decrease in density of large spines contributes to memory and/or cognitive impairments associated with Alzheimer\'s disease. In some instances, an abnormality in dendritic spine morphology contributes to the pathogenesis of Alzheimer\'s disease. In some instances, a decrease in size of spine heads reduces the probability of a spine bearing a synapse. In some instances, an abnormality in synaptic function contributes to the pathogenesis of Alzheimer\'s disease. In some instances, an abnormality in dendritic spine density and/or dendritic morphology and/or synaptic function is associated with activation of p21-activated kinase (PAK). In some instances, modulation of PAK activity (e.g., inhibition or partial inhibition of PAK) reverses or reduces abnormalities in dendritic spine morphology and/or dendritic spine density and/or synaptic function.

A dendritic spine is a small membranous protrusion from a neuron\'s dendrite that serves as a specialized structure for the formation, maintenance, and/or function of synapses. Dendritic spines vary in size and shape. In some instances, spines have a bulbous head (the spine head) of varying shape, and a thin neck that connects the head of the spine to the shaft of the dendrite. In some instances, spine numbers and shape are regulated by physiological and pathological events. In some instances, a dendritic spine head is a site of synaptic contact. In some instances, a dendritic spine shaft is a site of synaptic contact. FIG. 3 shows examples of different shapes of dendritic spines. Dendritic spines are “plastic.” In other words, spines are dynamic and continually change in shape, volume, and number in a highly regulated process. In some instances, spines change in shape, volume, length, thickness or number in a few hours. In some instances, spines change in shape, volume, length, thickness or number occurs within a few minutes. In some instances, spines change in shape, volume, length, thickness or number occurs in response to synaptic transmission and/or induction of synaptic plasticity. By way of example, dendritic spines are headless (filopodia as shown, for example, in FIG. 3a), thin (for example, as shown in FIG. 3b), stubby (for example as shown in FIG. 3c), mushroom-shaped (have door-knob heads with thick necks, for example as shown in FIG. 3d), ellipsoid (have prolate spheroid heads with thin necks, for example as shown in FIG. 3e), flattened (flattened heads with thin neck, for example as shown in FIG. 3f) or branched (for example as shown in FIG. 3g).

In some instances, mature spines have variably-shaped bulbous tips or heads, ˜0.5-2 μm in diameter, connected to a parent dendrite by thin stalks 0.1-1 μm long. In some instances, an immature dendritic spine is filopodia-like, with a length of 1.5-4 μm and no detectable spine head. In some instances, spine density ranges from 1 to 10 spines per micrometer length of dendrite, and varies with maturational stage of the spine and/or the neuronal cell. In some instances, dendritic spine density ranges from 1 to 40 spines per 10 micrometer in medium spiny neurons.

In some instances, the shape of the dendritic spine head determines synpatic function. Defects in dendritic spine morphology and/or function have been described in neurological diseases. In some instances, dendritic spines with larger spine head diameter form more stable synapses compared with dendritic spines with smaller head diameter. In some instances, a mushroom-shaped spine head is associated with normal or partially normal synaptic function. In some instances, a mushroom-shaped spine is a healthier spine (e.g., having normal or partially normal synapses) compared to a spine with a reduced spine head size, spine head volume and/or spine head diameter. In some instances, inhibition or partial inhibition of PAK activity results in an increase in spine head diameter and/or spine head volume and/or reduction of spine length, thereby normalizing or partially normalizing synaptic function in individuals suffering or suspected of suffering from Alzheimer\'s disease.

p21-Activated Kinases (PAKs)

The PAKs constitute a family of serine-threonine kinases that are composed of “conventional”, or Group I PAKs, that includes PAK1, PAK2, and PAK3, and “non-conventional”, or Group II PAKs, that includes PAK-4, PAK5, and PAK6. See, e.g., Zhao et al. (2005), Biochem J, 386:201-214. These kinases function downstream of the small GTPases Rac and/or Cdc42 to regulate multiple cellular functions, including dendritic morphogenesis and maintenance (see, e.g., Ethell et al (2005), Prog in Neurobiol, 75:161-205; Penzes et al (2003), Neuron, 37:263-274), motility, morphogenesis, angiogenesis, and apoptosis, (see, e.g., Bokoch et al., 2003, Annu. Rev. Biochem., 72:743; and Hofmann et al., 2004, J. Cell Sci., 117:4343;). GTP-bound Rac and/or Cdc42 bind to inactive PAK, releasing steric constraints imposed by a PAK autoinhibitory domain and/or permitting PAK phosphorylation and/or activation. Numerous phosphorylation sites have been identified that serve as markers for activated PAK.

In some instances, upstream effectors of PAK include, but are not limited to, TrkB receptors; NMDA receptors; adenosine receptors; estrogen receptors; integrins, EphB receptors; CDK5, FMRP; Rho-family GTPases, including Cdc42, Rac (including but not limited to Rac1 and Rac2), Chp, TC10, and Wrnch-1; guanine nucleotide exchange factors (“GEFs”), such as but not limited to GEFT, α-p-2′-activated kinase interacting exchange factor (αPIX), Kalirin-7, and Tiam1; G protein-coupled receptor kinase-interacting protein 1 (GIT1), and sphingosine.

In some instances, downstream effectors of PAK include, but are not limited to, substrates of PAK kinase, such as Myosin light chain kinase (MLCK), cofilin, cortactin, regulatory Myosin light chain (R-MLC), Myosins I heavy chain, myosin II heavy chain, Myosin VI, Caldesmon, Desmin, Op18/stathmin, Merlin, Filamin A, LIM kinase (LIMK), cortactin, cofilin, Ras, Raf, Mek, p47phox, BAD, caspase 3, estrogen and/or progesterone receptors, RhoGEF, GEF-H1, NET1, Gαz, phosphoglycerate mutase-B, RhoGDI, prolactin, p41Arc, cortactin and/or Aurora-A (See, e.g., Bokoch et al., 2003, Annu. Rev. Biochem., 72:743; and Hofmann et al., 2004, J. Cell Sci., 117:4343). Other substances that bind to PAK in cells include CIB; sphingolipids; lysophosphatidic acid, G-protein β and/or γ subunits; PIX/COOL; GIT/PKL; Nef; Paxillin; NESH; 5H3-containing proteins (e.g. Nck and/or Grb2); kinases (e.g. Akt, PDK1, PI 3-kinase/p85, Cdk5, Cdc2, Src kinases, Abl, and/or protein kinase A (PKA)); and/or phosphatases (e.g. phosphatase PP2A, POPX1, and/or POPX2).

Described herein are PAK inhibitors that treat one or more symptoms associated with Alzheimer\'s disease. Also described herein are pharmaceutical compositions comprising a PAK inhibitor (e.g., a PAK inhibitor compound described herein) for treatment of one or more symptoms of Alzheimer\'s disease. Also described herein is the use of a PAK inhibitor for manufacture of a medicament for treatment of one or more symptoms of Alzheimer\'s disease. In some embodiments, PAK inhibitors and compositions thereof treat negative symptoms and/or cognitive impairment associated with Alzheimer\'s disease.

In some embodiments, the PAK inhibitor is a Group I PAK inhibitor that inhibits, for example, one or more Group I PAK polypeptides, for example, PAK1, PAK2, and/or PAK3. In some embodiments, the PAK inhibitor is a PAK1 inhibitor. In some embodiments, the PAK inhibitor is a PAK2 inhibitor. In some embodiments, the PAK inhibitor is a PAK3 inhibitor. In some embodiments, the PAK inhibitor is a mixed PAK1/PAK3 inhibitor. In some embodiments, the PAK inhibitor inhibits all three Group I PAK isoforms (PAK1, 2 and PAK3) with equal or similar potency. In some embodiments, the PAK inhibitor is a Group II PAK inhibitor that inhibits one or more Group II PAK polypeptides, for example PAK4, PAK5, and/or PAK6. In some embodiments, the PAK inhibitor is a PAK4 inhibitor. In some embodiments, the PAK inhibitor is a PAK5 inhibitor. In some embodiments, the PAK inhibitor is a PAK6 inhibitor.

In some embodiments, a PAK inhibitor described herein reduces or inhibits the activity of one or more of PAK1, PAK2 and/or PAK3 while not affecting the activity of PAK4, PAK5 and/or PaK6. In some embodiments, a PAK inhibitor described herein reduces or inhibits the activity of one or more of PAK1, PAK2, PAK3, and/or PAK4. In some embodiments, a PAK inhibitor described herein reduces or inhibits the activity of one or more of PAK1, PAK2, PAK3, and/or one or more of PAK4, PAK5 and/or PAK6. In some embodiments, a PAK inhibitor described herein is a substantially complete inhibitor of one or more PAKs. As used herein, “substantially complete inhibition” means, for example, >95% inhibition of one or more targeted PAKs. In other embodiments, “substantially complete inhibition” means, for example, >90% inhibition of one or more targeted PAKs. In some other embodiments, “substantially complete inhibition” means, for example, >80% inhibition of one or more targeted PAKs. In some embodiments, a PAK inhibitor described herein is a partial inhibitor of one or more PAKs. As used herein, “partial inhibition” means, for example, between about 40% to about 60% inhibition of one or more targeted PAKs. In other embodiments, “partial inhibition” means, for example, between about 50% to about 70% inhibition of one or more targeted PAKs.

In some embodiments, a PAK inhibitor suitable for the methods described herein is a compound having the structure of Formula I or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R6 is —CN, —OH, substituted or unsubstituted alkoxy, —N(R10)2, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is halogen, —CN, —OH, substituted or unsubstituted alkoxy, —C(═O)N(R10)2, —CO2R10, —N(R10)2, acyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Q is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A is substituted or unsubstituted aryl or heteroaryl substituted with 0-4 R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —N R10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl; R9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl each R10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R10 together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl substituted with R5; each R5 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —NR10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; r is 0-8.

In some embodiments, a PAK inhibitor suitable for the methods described herein is a compound having the structure of Formula II or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R6 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is H, halogen, —CN, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)N(R10)2, —CO2R10, —N(R10)2, acyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Q is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A is substituted or unsubstituted aryl or heteroaryl substituted with 0-4 R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —N R10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl; R9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl each R10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R10 together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl substituted with R5; each R5 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —NR10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; r is 0-8.

In some embodiments, a PAK inhibitor suitable for the methods described herein is a compound having the structure of Formula III or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R6 is H, or halogen; R7 is acyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; Q is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A is substituted or unsubstituted aryl or heteroaryl substituted with 0-4 R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —N R10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl; R9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl each R10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R10 together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl substituted with R5; each R5 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —NR10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; r is 0-8.

In some embodiments, a PAK inhibitor suitable for the methods described herein is a compound having the structure of Formula IV or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R6 is substituted or unsubstituted alkyl; R7 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; Q is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A is substituted or unsubstituted aryl or heteroaryl substituted with 0-4 R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —N R10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl; R9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl each R10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R10 together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl substituted with R5; each R5 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —NR10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; r is 0-8.

In some embodiments, a PAK inhibitor suitable for the methods described herein is a compound having the structure of Formula V or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R6 is H, or halogen; R7 is H, halogen, CN, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)N(R10)2, CO2R10, N(R10)2, acyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Q is substituted or unsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A is substituted or unsubstituted aryl or heteroaryl substituted with 0-4 R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —N R10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl; R9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl each R10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R10 together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl substituted with R5; each R5 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R10, —NR10C(═O)OR10, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; r is 0-8.

In some embodiments, the compound of Formula V has the structure of Formula VI:

wherein: each of Y3, Y4 and Y5 are independently N—R1a, CR1R2, SO2, or C═O; R1a is H or substituted or unsubstituted alkyl; R1 and R2 are each independently H or substituted or unsubstituted alkyl.

In some embodiments, the compound of Formula V has the structure of Formula VIII:

wherein: ring A is an aryl or heteroaryl substituted with R4; each R4 is independently halogen, —CN, —NO2, —OH, —SR8, —S(═O)R9, —S(═O)2R9, —NR10S(═O)2R9, —S(═O)2N(R10)2, —C(═O)R9, —OC(═O)R9, —CO2R10, —N(R10)2, —C(═O)N(R10)2, —NR10C(═O)R9, —NR10C(═O)OR9, —NR10C(═O)N(R10)2, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; R8 is H or substituted or unsubstituted alkyl;

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